Oxycodone and its hydrochloride salt have long been used as analgesics.
Typically, oxycodone base is prepared by oxidation of thebaine to 14-hydroxycodeinone, and reducing the 14-hydroxycodeinone to oxycodone base. A route for the preparation of oxycodone via oxidation of thebaine to 14-hydroxycodeinone is illustrated in Scheme 1:

Once the oxycodone base has been prepared, it is usually reacted with an acid to produce an oxycodone salt, typically oxycodone hydrochloride (which is the API form in which oxycodone is generally used therapeutically), as shown below in Scheme 2:

The oxidation step in the synthetic route illustrated in Scheme 1 can yield by-products which may be converted into other by-products during further conversion of the oxidation product (e.g., during the reaction shown in Scheme 2) or may be carried over into the final oxycodone salt or other opioid made from the oxycodone base, final pharmaceutical composition or final dosage form. These by-products may be undesired in the final pharmaceutical composition or final dosage form. Separation of these by-products from the final product may often be difficult, time-consuming and not volume efficient (e.g., if a separation by HPLC is required).
For example, during oxidation of thebaine to 14-hydroxycodeinone, certain by-products can be formed, in particular 8-hydroxyoxycodone:

8-Hydroxyoxycodone can have two stereoconfigurations, 8α-hydroxyoxycodone (8-alpha-hydroxyoxycodone) and 8β-hydroxyoxycodone (8-beta-hydroxyoxycodone). It is known from the prior art that 8α-hydroxyoxycodone can convert to 14-hydroxycodeinone under acidic conditions (e.g., when HCl is added) (WO 2005/097801 to Chapman et al.). It is further known that, under harsher reaction conditions, 8β-hydroxyoxycodone can also convert to 14-hydroxycodeinone (Weiss U., J. Org. Chem. 22(1957), pp. 1505 to 1508). These conversions described in the art are illustrated in Scheme 4:

Thus, the 14-hydroxycodeinone intermediate shown in Scheme 1 is not only the immediate precursor to oxycodone, it is also often found in the final oxycodone salt used in pharmaceutical compositions, which is usually oxycodone hydrochloride. 14-hydroxycodeinone belongs to a class of compounds known as α,β-unsaturated ketones (ABUKs). These compounds contain a substructural component (the α,β-unsaturated ketone component) which produces a structure-activity relationship alert for genotoxicity. Some regulatory authorities do not approve a pharmaceutical composition or dosage form for use and sale to the public if the amount of 14-hydroxycodeinone in the pharmaceutical composition or dosage form exceeds the amount set by these authorities. The United States Food and Drug Administration (“FDA”) currently requires that, in order to obtain approval to market single-entity oxycodone HCl products, applicants must limit the level of ABUKs in oxycodone hydrochloride to NMT 10 ppm (not more than 10 ppm) of the oxycodone hydrochloride. In PCT/IB2013/001538 reactions are described which allow reduction of the amount of undesired by-products caused by the oxidation step. In particular, PCT/IB2013/001538 describes the performance of the oxidation reaction in the presence of an acid HnXn−, e.g. H2SO4, such that a 14-hydroxycodeinone salt with Xn−, e.g. SO42−, as counterion is formed:

However, even under these reaction conditions, some 8-hydroxyoxycodone might be carried over into oxycodone in a subsequent reduction reaction.
Even in spite of the improvements achieved by recent developments like the processes described in PCT/IB2013/001538, there is still a continuing need for processes for preparing oxycodone which exhibit a reduced amount of by-products in the final product. In particular, a process for preparing oxycodone base with a reduced amount of 8-hydroxyoxycodone, preferably with no (detectable) 8-hydroxyoxycodone would be advantageous.